Formulations decreasing particle exhalation

ABSTRACT

Formulations have been developed for pulmonary delivery to treat or reduce the infectivity of diseases such as viral infections, especially tuberculosis, SARS, influenza and respiratory synticial virus in humans and hoof and mouth disease in animals, or to reduce the symptoms of allergy or other pulmonary disease. Formulations for pulmonary administration include a material that significantly alters physical properties such as surface tension and surface elasticity of lung mucus lining fluid, which may be isotonic saline and, optionally, a carrier. The formulation may be administered as a liquid solution, suspension, aerosol, or powder where the particles consist basically of an osmotically active solute. Drugs, especially antivirals or antibiotics, may optionally be included with the formulation. These may be administered with or incorporated into the formulation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.10/990,996, filed Nov. 17, 2004, which in turn claims priority from U.S.provisional application Ser. No. 60/579,425, filed Jun. 14, 2004; U.S.provisional application Ser. No. 60/572,631, filed May 19, 2004; U.S.provisional application Ser. No. 60/564,189, filed Apr. 21, 2004; U.S.provisional application Ser. No. 60/560,470, filed Apr. 7, 2004; andU.S. provisional application Ser. No. 60/550,601, filed Mar. 5, 2004.

FIELD OF THE INVENTION

The present invention is in the field of formulations and systems todecrease the incidence of bioaerosol exhalation.

BACKGROUND OF THE INVENTION

Viral and bacterial infections are frequently highly contagious,especially when spread by respiration. The recent reports regardingSevere Acute Respiratory Syndrome (“SARS”), now known to be caused by acorona virus, are proof of how rapidly an infection can spread when itis transmitted through air contact. Other diseases such as influenzaspread by air contact, and rapidly reach epidemic proportions, with highnumbers of fatalities in elderly and immunocompromised populations.

SARS is a respiratory illness that has recently been reported in Asia,North America, and Europe. As of Apr. 20, 2003, about 198 suspect casesof SARS and 38 probable cases of SARS had been reported in the UnitedStates. In general, SARS begins with a fever greater than 100.4° F.[>38.0° C.]. Other symptoms may include headache, an overall feeling ofdiscomfort, and body aches. Some people also experience mild respiratorysymptoms. After 2 to 7 days, SARS patients may develop a dry cough andhave trouble breathing.

SARS appears to spread primarily by close person-to-person contact. MostSARS cases have involved people who cared for or lived with someone withSARS, or had direct contact with infectious material (for example,respiratory secretions) from a person who has SARS. Potential ways inwhich SARS can be spread include touching the skin of other people orobjects that are contaminated with infectious droplets and then touchingyour eye(s), nose, or mouth. This can happen when someone who is sickwith SARS coughs or sneezes droplets onto themselves, other people, ornearby surfaces. It is also possible that SARS can be spread morebroadly through the air or by other ways that are currently not known.At present there is no treatment or means of prevention for SARS, otherthan supportive care.

TB, or tuberculosis, is a disease caused by the bacteria Mycobacteriumtuberculosis. The bacteria can attack any part of the body, but usuallyattacks the lungs. TB was once the leading cause of death in the UnitedStates. In the 1940s, scientists discovered the first of several drugsnow used to treat TB. As a result, TB slowly began to disappear in theUnited States. Recently, TB has made a resurgence. Between 1985 and1992, the number of TB cases increased, with more than 16,000 casesreported in the United States in 2000 alone.

TB is spread through the air from one person to another. The bacteriaare dispersed into the air when a person with TB of the lungs or throatcoughs or sneezes. People nearby may breathe in these bacteria andbecome infected. When a person breathes in Mycobacterium tuberculosis,the bacteria can settle in the lungs and begin to grow. From there, itcan spread through the blood to other parts of the body, such as thekidney, spine, and brain. People with TB are most likely to spread it topeople they come in contact with on a daily basis. People who areinfected with latent TB do not feel sick, are asymptomatic, and cannotspread TB, but they may develop TB at some time in the future.

Bacteria are not the only sources of infectious diseases. Viruses arealso highly contagious and have no effective treatments other thancontainment. For example, Respiratory syncytial virus (RSV) is a verycommon virus that causes mild cold-like symptoms in adults and olderhealthy children. By age two, nearly all infants have been infected byRSV. RSV can cause severe respiratory infections in infants,particularly those born prematurely, with heart or lung disease, orimmunocompromised. Seasonal outbreaks of acute respiratory illnesstypically occur in the fall and last into the spring. RSV is spreadeasily by physical contact. Transmission is usually by contact withcontaminated secretions, called foamites, which may involve tinydroplets or objects that droplets have touched. RSV can live for half anhour or more on human hands. The virus can also live up to five hours oncountertops and for several hours on used tissues. RSV often spreadsvery rapidly in crowded households and day care centers. Each year up to125,000 infants are hospitalized due to severe RSV disease, and about1-2% of these infants die. It has been reported that exogenoussurfactant supplementation in infants with respiratory syncytial virusbronchiolitis was beneficial (Tibby, et al. Am J Respir Crit Care MedOctober 2000; 162(4 Pt 1):1251). The principle means of treatmentremains supportive however, and there is no means of limiting spreadother than isolation.

Influenza is another common viral infection for which there is noeffective treatment, and containment is the only option to limit spreadof disease. Influenza is caused by three viruses—Influenza A, B and C.Type A is usually responsible for large outbreaks and is most adept atmutating. New strains of Type A virus develop regularly and cause newepidemics every few years. Type B causes smaller outbreaks, and Type Cusually causes mild illness. In the United States, infection withinfluenza A and B leads to 20,000 deaths and over 100,000hospitalizations each year. Influenza is transmitted person to personvia contagious droplets that are formed when someone sneezes or coughs.

Approximately 8 million children and adolescents between 6 months and 17years of age have one or more medical conditions that put them atincreased risk of influenza-related complications. Such children includethose with chronic disorders of the heart or lungs (such as asthma andcystic fibrosis), children who have required regular medical follow-upor hospitalization during the preceding year because of chronicmetabolic diseases (including diabetes mellitus), kidney dysfunction,sickle cell anemia, or immunosuppression.

For unvaccinated individuals who have been exposed to people with knowninfluenza, especially if the exposed individual has risk factors,potential use of antiviral medication for more than 2 weeks andvaccination may help prevent illness. For mild illness in people who arenot at high-risk, the treatment of influenza is frequently justsupportive and includes bed rest, analgesics for muscle aches and pains,and increased intake of fluids. Treatment is usually not necessary forchildren, but may be prescribed if the illness is diagnosed early andthe patient is at risk of progression to more severe infection. Amongindividuals in high-risk groups (elderly, immunosuppressed, chronicheart, lung or kidney conditions) influenza may be quite severe and canlead to complications or death.

Epidemics of respiratory infections are not limited to humans.Foot-and-mouth disease virus (FMDV) is the etiologic agent offoot-and-mouth disease (FMD), which is a disease of cattle, swine, andother cloven-footed animals. FMD is characterized by the formation ofvesicles on the tongue, nose, muzzle, and coronary bands of infectedanimals. Several unique characteristics make the virus one of the mosteconomically devastating diseases in the world today. The ease withwhich it may be transmitted by contact and aerosol, combined with itsenhanced ability to initiate infections, virtually ensures that most, ifnot all, animals in a herd will contract FMD. The long-term survival ofFMDV in infected animals' tissues and organs, especially whenrefrigerated, offers an opportunity for its national and internationaltransmission through the food chain. Multiple serotypes and numeroussubtypes reduce the effectiveness and reliability of vaccines. Thepossible development of carriers in vaccinated animals and those thathave recovered from FMD provides additional potential sources of newoutbreaks. These features create a disease that can have a majoreconomic impact on live stock operations around the world. The foot andmouth disease (FMD) epidemic in British livestock remains an ongoingcause for concern, with new cases still arising in previously unaffectedareas (Ferguson, et al., Nature 2001 414(6861):329). The parameterestimates obtained in a dynamic model of disease spreading show thatextended culling programs were essential for controlling the epidemic tothe extent achieved, but demonstrate that the epidemic could have beensubstantially reduced in scale had the most efficient methods been usedearlier in the outbreak.

Viral shedding through bioaerosol exhalation is one mechanism, forinfection transmission from a host leading to inhalation by anotheranimal or human. The devastating consequences that uncontrolled viralshedding can have on livestock were seen in the hoof and mouth diseaseoutbreak in the U.K., where 2030 confirmed cases resulted in themandatory slaughter of 4 million animals. Recently, more attention isbeing given to the threat of bioterrorism and the similar risk that asudden outbreak of disease poses to livestock in the U.S.

Airborne infection is one of the main routes of pathogen transmission.Aerosols composed of mucus droplets originating in the lungs and nasalcavities are produced when a human or animal coughs or simply breathes.These bioaerosols can contain pathogens that transmit the disease uponinhalation by exposed humans or animals. In addition, respirablepathogenic bioaerosols produced in the upper airways can be re-breathedby the host leading to parenchymal infection with exacerbated diseaseoutcomes.

WO03/092654 to David Edwards et al. describes a method for diminishingthe spread of inhaled infections by delivering materials such assurfactants that suppress bioaerosol expiration. This technique works onthe basis of altering the surface or other physical properties of theendogenous surfactant fluid in the lungs, and thereby favoring fewerexhaled bioaerosol particles. It would be desirable to have other meansof limiting bioaerosol formation and/or spread.

It is therefore an object of the present invention to provideformulations for use in decreasing or limiting spread of pulmonaryinfections, especially viral or bacterial infections, without deliveryof surfactant material to the lungs.

It is further an object of the present invention to provide a method oftreatment to decrease or limit the spread of pulmonary infections toother animals or humans, especially viral or bacterial infections.

It is further an object of the present invention to provide a method oftreatment to decrease or limit the spread of pulmonary infections,especially viral or bacterial infections, within a patient.

It is further an object of the present invention to provide formulationsfor treatment of humans or animals to limit infectivity.

It is yet a further object of this invention to manufacture a device forthe measurement of exhaled particle number and particle size to diagnosethose animals or humans, with an enhanced propensity to exhale aerosols.

SUMMARY OF THE INVENTION

Formulations have been developed for delivery by any route to reduce theinfectivity of diseases such as viral infections, especiallytuberculosis, SARS, influenza, cytomegalovirus and RSV in humans andhoof and mouth disease in animals. In one embodiment, the formulationfor administration is a non-surfactant solution that, via dilution ofendogenous surfactant fluid, alters physical properties such as surfacetension, surface elasticity and bulk viscosity of lung mucus liningfluid. The aerosolized material may be an isotonic saline solution, ahypertonic saline solution or other solution containing osmoticallyactive materials. The formulation may be administered as a powder wherethe particles consist essentially of a salt or osmotically-activesubstance that dilutes endogenous surfactant fluid. The aerosol may be asolution, suspension, spray, mist, vapor, droplets, particles, or a drypowder, for example, using a metered dose inhaler including HFApropellant, a metered dose inhaler with non-HFA propellant, a nebulizer,a pressurized can, or a continuous sprayer. The aerosol is preferably anaqueous solution, and more preferably isotonic saline, or it may containa particularly effective osmotically-active substance, like mannitol.The formulation may be an organic suspension or solution for aerosoldelivery. The formulation may be a vapor. Typical concentrations ofsalts or sugars are in the range of up to 5 or 6% solute. In a preferredembodiment, the formulations are administered either as a powder oraerosol, preferably prior to or shortly after infection, allergy orasthma attack. The formulations are administered to decrease or preventexhalation of particulate matter, especially of infectious particulatematter. The formulation is administered in an amount sufficient todecrease surface instabilities in the liquid lining the airways of thelung, i.e., to damp the rate of droplet formation from lung fluid,without causing expectoration. Examples demonstrate suitableformulations and effective amounts. An example demonstrates efficacy ofadministration of nebulized saline over a period of up to twelveminutes, preferably two minutes or greater, to decrease particleexhalation in cattle.

A method of screening animals or humans for a number of characteristics,including the measurement of expired air and inspired air, theassessment of exhaled particle numbers, the assessment of exhaledparticle size and the assessment of tidal volume and respiratoryfrequency during sampling, was devised to aid in the diagnosis ofanimals or humans who have an enhanced propensity to exhale aerosols. Adevice with sufficient sensitivity to accurately count sub-micron sizedparticles was designed and assembled. The device is portable andoperates on batteries. Particle number and size can be determined byinfrared spectroscopy, laser diffraction or light scattering.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram of the simulated cough machine apparatus.

FIG. 2 illustrates an actual cough profile versus a simulated coughprofile.

FIG. 3 illustrates particle concentration following three coughsmeasured over time for plain mucus simulant and following salinedelivery at t=0, t=30 and t=60 minutes.

FIG. 4A is a chart of baseline particle count (greater than 150 nm)expired by individuals (n=11) while inhaling particle free air; and FIG.4B is a graph of particle count (greater than 150 nm) expired byindividuals (n=11) after saline (approximately 1 g) had beenadministered to the lungs in the form of an aerosol over time (minutes).

FIG. 5A is a graph of particle count (greater than 150 nm) exhaled byindividuals (n=2) who, prior to treatment have a baseline exhalation ofgreater than 1000 particles/liter (while inhaling particle free air),after isotonic saline solution (approximately 1 g solution) had beenadministered to the lungs in the form of an aerosol over time (minutes);and FIG. 5B is a graph of particle count (greater than 150 nm) exhaledby individuals (n=2) who, prior to treatment have a baseline exhalationof greater than 1000 particles/liter (while inhaling particle free air),after isotonic saline solution containing phospholipids (approximately 1g solution) had been administered to the lungs in the form of an aerosolover time (minutes).

FIG. 6A is a graph of total particles exhaled (greater than 0.3 microns)over time (minutes) showing data obtained from sham treated animals.FIG. 8B is a graph of mean percent (%) baseline particle counts overtime (minutes) showing data obtained from animals treated with nebulizedsaline for 1.8 minutes (-▪-), 6.0 minutes (-▴-), 12.0 minutes (-□-), andsham (-♦-).

DETAILED DESCRIPTION OF THE INVENTION

Lung mucociliary clearance is the primary mechanism by which the airwaysare kept clean from particles present in the liquid film that coatsthem. The conducting airways are lined with ciliated epithelium thatbeat to drive a layer of mucus towards the larynx, clearing the airwaysfrom the lowest ciliated region in 24 hours. The fluid coating consistsof water, sugars, proteins, glycoproteins, and lipids. It is generatedin the airway epithelium and the submucosal glands, and the thickness ofthe layer ranges from several microns in the trachea to approximately 1micron in the distal airways in humans, rat, and guinea pig.

A second important mechanism for keeping the lungs clean is via momentumtransfer from the air flowing through the lungs to the mucus coating.Coughing increases this momentum transfer and is used by the body to aidthe removal of excess mucus. It becomes important when mucus cannot beadequately removed by ciliary beating alone, as occurs in mucushypersecretion associated with many disease states. Air speeds as highas 200 m/s can be generated during a forceful cough. The onset ofunstable sinusoidal disturbances at the mucus layer has been observed atsuch air speeds. This disturbance results in enhanced momentum transferfrom the air to the mucus and consequently accelerates the rate of mucusclearance from the lungs. Experiments have shown that this disturbanceis initiated when the air speed exceeds some critical value that is afunction of film thickness, surface tension, and viscosity (M.Gad-El-Hák, R. F. Blackwelder, J. J. Riley. J. Fluid Mech.—(1984)140:257-280). Theoretical predictions and experiments with mucus-likefilms suggest that the critical speed to initiate wave disturbances inthe lungs is in the range of 5-30 m/s.

Papineni and Rosenthal (J. Aerosol Med., 1997, 10(2): 105-116) havedemonstrated that during standard mouth and nose breathing, or duringcoughing, normal human subjects expire tens to hundreds of liquidbioaerosol droplets, with a preponderance of exhaled bioaerosol dropletshaving a diameter smaller than one micron. Coughing was shown to giverise to the greatest number of particles, although the mean exhaledparticle size remained significantly less than a micron. The majority ofthese particles are larger than most inhaled pathogens, i.e., greaterthan 150 nm. For instance, some common inhaled pathogens havecharacteristic sizes in this range: tuberculosis, 1,000-5,000 nm;influenza, 80-120 nm; measles, 100-250 nm; chicken pox, 120-200 nm; FMD,27-30 nm.

I. Formulations

Bioaerosol particles are formed by instabilities in the endogenoussurfactant layer in the airways. This instability depends on endogenoussurfactant concentration in the lungs. This surfactant concentration canbe altered by simply diluting the endogenous surfactant pool via eitherdelivery of isotonic saline (though not in such a large amount as tocause a subject to expectorate) or a hypertonic saline solution thatcauses the cells lining the lung's airways to dilute further theendogenous surfactant layer via production of water.

The formulations described herein are effective to decrease aerosolexhalation, by preventing or reducing exhaled particle formation fromthe oropharynx or nasal cavities. A preferred aerosol solution foraltering physical properties of the lung's lining fluid is isotonicsaline. Saline solutions have long been delivered chronically to thelungs with small amounts of therapeutically active agents, such as betaagonists, corticosteroids, or antibiotics. For example, VENTOLIN®Inhalation Solution (GSK) is an albuterol sulfate solution used in thechronic treatment of asthma and exercise-induced bronchospasm symptoms.A VENTOLIN® solution for nebulization is prepared (by the patient) bymixing 1.25-2.5 mg of albuterol sulfate (in 0.25-0.5 mL of aqueoussolution) into sterile normal saline to achieve a total volume of 3 mL.No adverse effects are thought to be associated with the delivery ofsaline to the lungs by VENTOLIN® nebulization, even though nebulizationtimes can range from 5-15 minutes. Saline is also delivered in moresignificant amounts to induce expectoration. Often these salinesolutions are hypertonic (sodium chloride concentrations greater than0.9%, often as high as 5%) and generally they are delivered for up to 20minutes.

It has been discovered that physical properties of the endogenoussurfactant fluid in the lungs, such as surface tension, can be alteredby administration of a saline solution, as well as by administration ofan aqueous saline solution containing other materials, such assurfactant.

The term “aerosol” as used herein refers to any preparation of a finemist of particles, typically less than 10 microns in diameter, which canbe in solution or a suspension. The preferred mean diameter for aqueousformulation aerosol particles is about 3 microns, for example between0.1 and 30 microns, most preferably between 1 and 10 microns. Theaerosol can consist just of a solution, such as an aqueous solution,most preferably a saline solution. Alternatively, the aerosol mayconsist of an aqueous suspension or dry particles. Concentration rangesof the salt or other osmotically active material range from about 0.01%to about 10% by weight, preferably between 0.9% to about 10%.

A. Osmotically Active Materials

Many materials may be osmotically active, including binary salts, suchas sodium chloride, or any other kinds of salts, or sugars, such asmannitol. Osmotically active materials, normally owing to theirionization and possibly size, do not easily permeate cell membranes andtherefore exert an osmotic pressure on contiguous cells. Such osmoticpressure is essential to the physical environment of cellular material,and regulation of this pressure occurs by cell pumping of water into orout of the cell. Solutions delivered to the lungs that are isotonicnormally do not create an imbalance in osmotic pressure in the lungfluid and therefore simply dilute the natural endogenous lung fluid withwater and salt. Solutions of high osmotic content (i.e. hypertonicsolutions) create an imbalance of osmotic pressure, with greaterpressure in the lung fluid, causing cells to pump water into the lungfluid and therefore further dilute lung surfactant composition.

B. Active Ingredients

The formulations disclosed herein can be used by any route for deliveryof a variety of molecules, especially antivirals and anti-infectivemolecules including antibiotics, antihistamines, bronchodilators, coughsuppressants, anti-inflammatories, vaccines, adjuvants and expectorants.Examples of macromolecules include proteins and large peptides,polysaccharides and oligosaccharides, and DNA and RNA nucleic acidmolecules and their analogs having therapeutic, prophylactic ordiagnostic activities. Nucleic acid molecules include genes, antisensemolecules that bind to complementary DNA to inhibit transcription, andribozymes. Preferred agents are antiviral, steroid, bronchodilators,antibiotics, mucus production inhibitors and vaccines.

In the preferred embodiment, the concentration of the active agentranges from about 0.01% to about 20% by weight. In a more preferredembodiment, the concentration of active agent ranges from between 0.9%to about 10%.

II. Carriers and Aerosols for Administration

Carriers can be divided into those for administration via solutions(liquid formulations) and those for administration via particles (drypowder formulations).

A. Liquid Formulations

Aerosols for the delivery of therapeutic agents to the respiratory tracthave been developed. See, for example, Adjei, A. and Garren, J. Pharm.Res., 7: 565-569 (1990); and Zanen, P. and Lamm, J.-W. J. Int. J.Pharm., 114: 111-115 (1995). These are typically formed by atomizing thesolution or suspension under pressure through a nebulizer or through theuse of a metered dose inhaler (“MDI”). In the preferred embodiment,these are aqueous solutions or suspensions.

B. Dry Powder Formulations

The geometry of the airways is a major barrier for drug dispersal withinthe lungs. The lungs are designed to entrap particles of foreign matterthat are breathed in, such as dust. There are three basic mechanisms ofdeposition: impaction, sedimentation, and Brownian motion (J. M.Padfield. 1987. In: D. Ganderton & T. Jones eds. Drug Delivery to theRespiratory Tract, Ellis Harwood, Chicherster, U.K.). Impaction occurswhen particles are unable to stay within the air stream, particularly atairway branches. They are adsorbed onto the mucus layer coveringbronchial walls and cleaned out by mucocilliary action. Impaction mostlyoccurs with particles over 5 μm in diameter. Smaller particles (<5 μm)can stay within the air stream and be transported deep into the lungs.Sedimentation often occurs in the lower respiratory system where airflowis slower. Very small particles (<0.6 μm) can deposit by Brownianmotion. This regime is undesirable because deposition cannot be targetedto the alveoli (N. Worakul & J. R. Robinson. 2002. In: PolymericBiomaterials, 2^(nd) ed. S. Dumitriu ed. Marcel Dekker: New York).

The preferred mean diameter for aerodynamically light particles forinhalation is at least about 5 microns, for example between about 5 and30 microns, most preferably between 3 and 7 microns in diameter. Theparticles may be fabricated with the appropriate material, surfaceroughness, diameter and tap density for localized delivery to selectedregions of the respiratory tract such as the deep lung or upper airways.For example, higher density or larger particles may be used for upperairway delivery. Similarly, a mixture of different sized particles,provided with the same or different therapeutic agent may beadministered to target different regions of the lung in oneadministration.

As used herein, the phrase “aerodynamically light particles” refers toparticles having a mean or tap density less than about 0.4 g/cm³. Thetap density of particles of a dry powder may be obtained by the standardUSP tap density measurement. Tap density is a standard measure of theenvelope mass density. The envelope mass density of an isotropicparticle is defined as the mass of the particle divided by the minimumsphere envelope volume in which it can be enclosed. Featurescontributing to low tap density include irregular surface texture andporous structure'.

Dry powder formulations (“DPFs”) with large particle size have improvedflowability characteristics, such as less aggregation (Visser, J.,Powder Technology 58: 1-10 (1989)), easier aerosolization, andpotentially less phagocytosis. Rudt, S. and R. H. Muller, J. ControlledRelease, 22: 263-272 (1992); Tabata, Y., and Y. Ikada, J. Biomed. Mater.Res., 22: 837-858 (1988). Dry powder aerosols for inhalation therapy aregenerally produced with mean diameters primarily in the range of lessthan 5 microns, although a preferred range is between one and tenmicrons in aerodynamic diameter. Ganderton, D., J. BiopharmaceuticalSciences, 3:101-105 (1992); Gonda, I. “Physico-Chemical Principles inAerosol Delivery,” in Topics in Pharmaceutical Sciences 1991, Crommelin,D. J. and K. K. Midha, Eds., Medpharm Scientific Publishers, Stuttgart,pp. 95-115 (1992). Large “carrier” particles (containing no drug) havebeen co-delivered with therapeutic aerosols to aid in achievingefficient aerosolization among other possible benefits. French, D. L.,Edwards, D. A. and Niven, R. W., J. Aerosol Sci., 27: 769-783 (1996).Particles with degradation and release times ranging from seconds tomonths can be designed and fabricated by established methods in the art.

Particles can consist of the osmotic agent, alone, or in combinationwith drug, surfactant, polymer, or combinations thereof. Representativesurfactants include L-alpha.-phosphatidylcholine dipalmitoyl (“DPPC”),diphosphatidyl glycerol (DPPG),1,2-Dipalmitoyl-sn-glycero-3-phospho-L-serine (DPPS),1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DSPC),1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE),1-palmitoyl-2-oleoylphosphatidylcholine (POPC), fatty alcohols,polyoxyethylene-9-lauryl ether, surface active fatty acids, sorbitantrioleate (Span 85), glycocholate, surfactin, poloxomers, sorbitan fattyacid esters, tyloxapol, phospholipids, and alkylated sugars. Polymersmay be tailored to optimize particle characteristics including: i)interactions between the agent to be delivered and the polymer toprovide stabilization of the agent and retention of activity upondelivery; ii) rate of polymer degradation and thus drug release profile;iii) surface characteristics and targeting capabilities via chemicalmodification; and iv) particle porosity. Polymeric particles may beprepared using single and double emulsion solvent evaporation, spraydrying, solvent extraction, solvent evaporation, phase separation,simple and complex coacervation, interfacial polymerization, and othermethods well known to those of ordinary skill in the art. Particles maybe made using methods for making microspheres or microcapsules known inthe art. The preferred methods of manufacture are by spray drying andfreeze drying, which entails using a solution containing the surfactant,spraying the solution onto a substrate to form droplets of the desiredsize, and removing the solvent.

III. Administration of Formulations to the Respiratory Tract

A. Methods of Administration

The respiratory tract is the structure involved in the exchange of gasesbetween the atmosphere and the blood stream. The lungs are branchingstructures ultimately ending with the alveoli where the exchange ofgases occurs. The alveolar surface area is the largest in therespiratory system and is where drug absorption occurs. The alveoli arecovered by a thin epithelium without cilia or a mucus blanket andsecrete surfactant phospholipids. J. S. Patton & R. M. Platz. 1992. Adv.Drug Del. Rev. 8:179-196

The respiratory tract encompasses the upper airways, including theoropharynx and larynx, followed by the lower airways, which include thetrachea followed by bifurcations into the bronchi and bronchioli. Theupper and lower airways are called the conducting airways. The terminalbronchioli then divide into respiratory bronchioli which lead to theultimate respiratory zone, the alveoli or deep lung. The deep lung, oralveoli, is the primary target of inhaled therapeutic aerosols forsystemic drug delivery.

The formulations are typically administered to an individual to deliveran effective amount to alter physical properties such as surface tensionand viscosity of endogenous fluid in the upper airways, therebyenhancing delivery to the lungs and/or suppressing coughing and/orimproving clearance from the lungs. Effectiveness can be measured usinga system as described below. For example, saline can be administered ina volume of 1 gram to a normal adult. Exhalation of particles is thenmeasured. Delivery is then optimized to minimize dose and particlenumber.

Formulations can be administered using a metered dose inhaler (“MDI”), anebulizer, an aerosolizer, or using a dry powder inhaler. Suitabledevices are commercially available and described in the literature.

Aerosol dosage, formulations and delivery systems may be selected for aparticular therapeutic application, as described, for example, in Gonda,I. “Aerosols for delivery of therapeutic and diagnostic agents to therespiratory tract,” in Critical Reviews in Therapeutic Drug CarrierSystems, 6:273-313, 1990; and in Moren, “Aerosol dosage forms andformulations,” in: Aerosols in Medicine, Principles, Diagnosis andTherapy, Moren, et al., Eds. Esevier, Amsterdam, 1985.

Delivery is achieved by one of several methods, for example, using ametered dose inhaler including HFA propellant, a metered dose inhalerwith non-HFA propellant, a nebulizer, a pressurized can, or a continuoussprayer. For example, the patient can mix a dried powder ofpre-suspended therapeutic with solvent and then nebulize it. It may bemore appropriate to use a pre-nebulized solution, regulating the dosageadministered and avoiding possible loss of suspension. Afternebulization, it may be possible to pressurize the aerosol and have itadministered through a metered dose inhaler (MDI). Nebulizers create afine mist from a solution or suspension, which is inhaled by thepatient. The devices described in U.S. Pat. No. 5,709,202 to Lloyd, etal., can be used. An MDI typically includes a pressurized canisterhaving a meter valve, wherein the canister is filled with the solutionor suspension and a propellant. The solvent itself may function as thepropellant, or the composition may be combined with a propellant, suchas FREON® (E. I. Du Pont De Nemours and Co. Corp.). The composition is afine mist when released from the canister due to the release inpressure. The propellant and solvent may wholly or partially evaporatedue to the decrease in pressure.

In an alternative embodiment, the formulation is in the form of salt orosmotically active material particles which are dispersed on or in aninert substrate, which is placed over the nose and/or mouth and theformulation particles inhaled. The inert substrate is preferably abiodegradable or disposable woven or non-woven fabric and morepreferably the fabric is formed of a cellulosic-type material. Anexample is tissues currently sold which contain lotion to minimizeirritation following frequent use. These formulations can be packagedand sold individually or in packages similar to tissue or baby wipepackages, which are easily adapted for use with a liquid solution orsuspension.

Individuals to be treated include those at risk of infection, those witha viral or bacterial infection, allergy patients, asthma patients, andindividuals working with immunocompromised patients or infectedpatients.

The formulation may be administered to humans or animals such asracehorses, breeding livestock, or endangered captive animals to protectthese animals from infection by viral shedding. This may be accomplishedby placing a nebulizer system near watering stations and triggeringproduction of the aerosol as animals either approach or leave thestation. Formulation may be sprayed over the animals as they walkthrough chutes or pens, or sprayed from spray trucks or even cropdusting type airplanes. Individual battery powered sprayers that arecurrently used to spray insecticides may be adapted for use inadministering the solutions to the animal§ to minimize bioaerosolformation and/or dispersion.

The formulation may be administered to humans or animals at the onset ofviral or bacterial outbreak to prevent spread of the disease to epidemiclevels. Animals within a 10-kilometer radius of a FMD outbreak arecurrently deemed infected. These animals are subsequently slaughteredand disinfected. This aerosol system may be administered immediately toanimals within this 10-kilometer radius zone and a further prescribedbuffer zone outside this area to assure containment of the outbreak. Theaerosol can then be administered for as long as is necessary to ensuresuccess, i.e. beyond the normal period between first infection andsymptom expression.

The formulation may be administered to humans or animals by creating anaqueous environment in which the humans and animals move or remain forsufficient periods of time to sufficiently hydrate the lungs. Thisatmosphere might be created by use of a nebulizer or even a humidifier.

Although described primarily with reference to pulmonary administration,it is understood that the formulations may be administered to individualanimals or humans through inhalation; parenteral, oral, rectal, vaginalor topical administration; or by administration to the ocular space.

IV. Methods and Devices for Screening for “Over Producers”

A. Methods

Diagnosis of animals or humans who have an enhanced propensity to exhaleaerosols (referred to herein as “over producers”, “super-producers”, or“superspreaders”) can be done by screening for a number of factorsincluding the measurement of expired air and inspired air, theassessment of exhaled particle numbers, the assessment of exhaledparticle size, the assessment of tidal volume and respiratory frequencyduring sampling, and the assessment of viral and bacterial infectivity.The assessment of exhaled particle numbers is done at a respiratory flowrate of about 10 to about 120 liters per minutes (LPM).

B. Devices

A device with sufficient sensitivity to accurately count sub-micronsized particles was designed and assembled as described in the examples.Preferably the device is portable and operates on batteries. Themeasurement of particle number and particle size can be done by infraredspectroscopy, laser diffraction, or light scattering

In Vitro Testing of Bioaerosol Transmission

The following in vitro method can be used to test the effectiveness ofdelivering saline or other solutions of an osmotically active materialon bioaerosol generation in the airways. A “cough machine” (M. King, J.M. Zahm, D. Pierrot, S. Vaquez-Girod, E. Puchelle. Biorheology. (1989)26:737-745) is used to control air speed experienced by simulated mucuslining of the airway. Labeled nanoparticles can be incorporated into thefluid, and a filter placed at the exit of the cough machine to collectthe aerosol droplets generated. A variety of compounds can be added toalter shear viscosity, elongational viscosity, and surface tension. Thetest is repeated at varying air velocities, below, including, and above25 m/s.

Toxicity Studies

Compounds to be administered can be tested for non-toxicity. Forexample, preliminary in vitro studies can be conducted to test thetoxicity of solutions upon addition to monolayers of fibroblast cells.NIH 3T3 fibroblasts are plated onto glass Lab-Tek™ coverslip chambers(NUNC, Rochester, N.Y.) and grown to confluence. The cells are thenexposed to a solution in 10% FBS DMEM for 10 seconds and returned to theincubator after several washes with 10% FBS in DMEM. After 15 minutesthe cells are exposed to 10 μM Cell-Tracker™ Green CMFDA (MolecularProbes, Eugene, Oreg.) for 30 min. The cells are then washed severaltimes with 10% FBS DMEM and placed in a 37° C., 5% CO₂ microscopechamber. The CMFDA stain readily enters the cell and if the cell isalive, the stain becomes enzymatically modified and cannot leave. Thusviable cells will fluoresce brightly while dead cells will not. Thecells are imaged with an inverted fluorescence microscope.

In vivo toxicity studies determine which of the most effectiveformulations of the in vitro studies are the least toxic. Animals willbe administered the prepared formulations and intravenous blood sampleswill be collected. Also, tracheal lavage will provide information aboutdamage to lung tissue resulting from administration of the preparations.

Treatment is continued for as long as there is risk of infection orspread of disease, with treatment repeated as necessary to prevent orlimit viral shedding. In the case of asthma, allergy and other pulmonarydisorders, treatment will be continued to maintain the desired pulmonaryparameters.

The present invention will be further understood by reference to thefollowing non-limiting examples.

EXAMPLES Example 1 In Vitro Simulation

As shown in FIG. 1, a simulated cough machine system was designedsimilar to that described by King Am. J. Respir. Crit. Care Med.156(1):173-7 (1997). An air-tight 6.25-liter Plexiglas tank equippedwith a digital pressure gauge and pressure relief valve was constructedto serve as the capacitance function of the lungs. To pressurize thetank, a grade dry compressed air cylinder with regulator was connectedto the inlet. At the outlet of the tank, an Asco two-way normally-closedsolenoid valve (8210G94) with a sufficient Cv flow factor was connectedfor gas release. The solenoid valve was wired using a typical 120V, 60Hz light switch. Connected to the outflow of the solenoid valve was aFleisch no. 4 pneumotachograph, which created a Poiseuille flow neededto examine the “cough” profile. The outlet of the Fleisch tube wasconnected to a ¼ NPT entrance to our model trachea. A Validyne DP45-14differential pressure transducer measured the pressure drop through theFleisch tube. A Validyne CD 15 sine wave carrier demodulator was used toamplify this signal to the data acquisition software. Weak polymericgels with rheological properties similar to tracheobronchial mucus wereprepared as described by King et al Nurs Res. 31(6):324-9 (1982). Locustbean gum (LBG) (Fluka BioChemika) solutions were crosslinked with sodiumtetraborate (Na₂B₄O₇) (J. T. Baker). LBG at 2% wt/vol was dissolved inboiling Milli-Q distilled water. A concentrated sodium tetraboratesolution was prepared in Milli-Q distilled water. After the LBG solutioncooled to room temperature, small amounts of sodium tetraborate solutionwere added and the mixture was slowly rotated for 1 minute. The stillwatery mucus simulant was then pipetted onto the model trachea creatingsimulant depth based on simple trough geometry. Mucus simulant layerswere allowed 30 minutes to crosslink prior to initiation of “cough”experiments. At this point, t=0 min, time points were measured, followedby t=30 min and t=60 min. Final concentrations of sodium tetraborateranged from 1-3 mM. An acrylic model trachea was designed 30 cm longwith interior width and height of 1.6 cm. The model trachea formed arectangular shaped tube with a separate top to fit, allowing for easyaccess to the mucus simulant layer. A gasket and C-clamps were used tocreate an air-tight seal. A rectangular cross-section was chosen toenable uniform mucus simulant height and to avoid problems associatedwith round tubes and gravity drainage. The cross-sectional area of themodel trachea was also physiologically relevant. The end of the modeltrachea remained open to the atmosphere. Nebulized solutions weredelivered to the mucus simulant via a PARI LC Jet nebulizer and PronebUltra compressor. Formulations included normal isotonic 0.9% saline(VWR) and 100 mg/mL of synthetic phospholipids1,2-Dipalmitoyl-sn-glycero-3-phosphocholine/1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol(DPPC/POPG) (Genzyme) 7/3 wt % suspended in isotonic saline. 3 mL of thechosen formulation was pipetted into the nebulizer and aerosolized untilnebulizer sputter through the open-ended but clamped model tracheatrough on the layer of mucus simulant. The model trachea was thenattached to the outlet of the Fleisch tube prior to t=0 min experiments.As well, t=30 min and t=60 min (post-dose) experiments were performed.

A Sympatec HELOS/KF laser diffraction particle sizer was used to sizethe created mucus simulant bioaerosols. The Fraunhoffer method forsizing diffracted particles was used. The HELOS was equipped with an R2submicron window module enabling a measuring range of 0.25-87.5 μm.Prior to “cough” experiments, the end of the model trachea was, adjustedto be no more than 3 cms from the laser beam. As well, the bottom of themodel trachea was aligned with the 2.2 mm laser beam using support jacksand levels. Dispersed bioaerosols were collected after passing throughthe diffraction beam using a vacuum connected to an inertial cyclonefollowed by a HEPA filter. Before each run, the laser was referenced for5 s to ambient conditions. Measurement began after a specified triggercondition of optical concentration (C_(opt))>0.2% and stopped 2 s afterC_(opt)≦0.2%. Sympatec WINDOX software was used to create cumulative anddensity distribution graphs versus log particle size by volume.

A typical cough profile, consisting of a biphasic burst of air, waspassed over the 1.5 mm layer of mucus simulant. The initial flow or airpossessed a flow rate of about 12 L/s for 30-50 ms. The second phaselasted 200-500 ms and then rapidly decayed. A representative actualcough profile is compared with a simulated cough profile (5 psi tankpressure) in FIG. 2.

Bioaerosol particle concentration following three coughs was measuredover time (FIG. 3) in the case of an undisturbed mucus simulant, and inthe cases of saline delivery (FIG. 3) and surfactant delivery (notshown). In the undisturbed case, bioaerosol particle size remainsconstant over time with a median size of about 400 nanometers. Followingthe addition of saline, bioaerosol particle size increases from 1 micron(t=0) to about 60 microns (t=30 min) and then diminishes to 30 microns(t=60 min).

These in vitro results show that saline delivered to a mucus layercauses a substantial increase in particle size on breakup, possiblyowing to an increase in surface tension. As indicated by the in vivoresults, the larger size droplets are less capable of exiting the mouth.Therefore, delivery of the solution serves to significantly lower thenumber of expired particles.

Example 2 Reduction of Exhaled Aerosol Particles in Human Study

A proof of concept study of exhaled aerosol particle production wasperformed using 12 healthy subjects. The objectives of the study were(1) to determine the nature of exhaled bioaerosol particles (sizedistribution and number); (2) to validate the utility of a device thatis sensitive enough to accurately count the exhaled particles; (3) toassess the baseline count of particles exhaled from the healthy lung;and (4) to measure the effect of two exogenously administered treatmentaerosols on exhaled particle count suppression. Experiments wereperformed with different particle detectors to determine averageparticles per liter and average particle size for healthy humansubjects. Following the inspiration of particle-free air, healthysubjects breathe out as little as 1-5 particles per liter, with anaverage size of 200-400 nm in diameter. Significant variations occur innumbers of particles from subject to subject, so that some subjectsexhale as many as 30,000 particles per liter, again predominantly ofsubmicron particle size. A device with sufficient sensitivity toaccurately count sub-micron sized particles was designed and assembled.The LASER component of the device was calibrated in accordance withmanufacturer procedures (Climet Instruments Company, Redlands, Calif.).This device accurately measured particles in the range of 150-500 nmwith a sensitivity of 1 particle/liter. A series of filters eliminatedall background particle noise.

Following protocol IRB approval, 12 healthy subjects were enrolled inthe study. Inclusion criteria were good health, age 18-65 years, normallung function (FEV₁ predicted>80%), informed consent and capability toperform the measurements. Exclusion criteria were presence or a historyof significant pulmonary disease (e.g. asthma, COPD, cystic fibrosis),cardiovascular disease, acute or chronic infection of the respiratorytract, and pregnant or lactating females. One individual was not able tocomplete the entire dosing regimen and therefore was excluded from thedata analysis.

Following a complete physical exam, the subjects were randomized intotwo groups: those to initially receive prototype formulation 1 and thoseto receive prototype formulation 2. Baseline exhaled particle productionwas measured after a two minute “wash out” period on the device. Theassessment was made over a two minute period with the per-minute countderived from the average of the two minutes. Following the baselinemeasurement, the prototype formulation was administered over a sixminute period using a commercial aqueous nebulizer (Pari RespiratoryEquipment, Starnberg, Germany). Formulation 1 consisted of an isotonicsaline solution. Formulation 2 consisted of a combination ofphospholipids suspended in an isotonic saline vehicle. Followingadministration, exhaled particle counts were assessed 5 minutes, 30minutes, one hour, two hours, and three hours after the singleadministration.

As shown in FIG. 4A, substantial inter-subject variability was found inbaseline particle counts. The data shown are measurements made prior toadministration of one of the test aerosols. This baseline expiredparticle result points to the existence of “super producers” of exhaledaerosols. In this study “super-producers” were defined as subjectsexhaling more than 1,000 particles/liter at baseline measurement. FIG.4B shows the individual particle counts for subjects receivingFormulation 1. The data indicate that a simple formulation ofexogenously applied aerosol can suppress exhaled particle counts.

FIG. 5A shows the effect of prototype formulation 1 on the two“super-producers” found at baseline in this group. These data indicatethat the prototype formulation may exert a more pronounced effect onsuper-producers.

Similar results were found on delivery of formulation 2. FIG. 5Bsummarizes the percent change (versus baseline) of the cumulativeexhaled particle counts for the “super-producers” identified in the twotreatment groups. Results from this study demonstrate that exhaledparticles can be accurately measured using a laser-detection system,that these particles are predominantly less than 1 micron in diameter,and that the number of these particles varies substantially from subjectto subject. “Super-producing” subjects respond most markedly to deliveryof an aerosol that modifies the physical properties of the surface ofthe lining fluid of the lungs. Such super-producers might bearsignificant responsibility for pathogen shedding and transmission in apopulation of infected patients. These data also demonstrate thatsuppressing aerosol exhalation is practical with relatively simple andsafe exogenously administered aerosol formulations.

Example 3 Large Animal Study

Seven (7) Holstein bull calves were anesthetized, intubated, andscreened for baseline particle exhalation by optical laser counting.Animals were subsequently untreated (sham) or treated with a nebulizedaerosol of saline at one of three doses (1.8 minutes, 6.0 minutes or12.0 minutes). During the sham dosage, the animals were handled in thesame manner as they were when the dosages of the isotonic salinesolution were administered. One animal was dosed per day and nebulizerdoses were randomized throughout the exposure period (see Table 1 fordosing schedule). Each animal was slated to receive all doses during theduration of the study. Following the administration of each dose,exhaled particle counts were monitored at discrete timepoints (0, 15,30, 45, 60, 90, 120) through 180 minutes.

The exposure matrix for the animals included in the study is found inTable 1. The dosing occurred over a 57 day period, with at least a 7 dayinterval between dosages. Each animal (n=7) received each dose at leastonce during the duration of dosing, with the exception of the omissionof one 6.0 minute dose (see animal no. 1736) and one 12.0 minute dose(see animal no. 1735). These two were excluded due to unexpectedproblems with the ventilator and/or anesthesia equipment. TABLE 1 DosingRegime for Large Animals Dosage Animal No. Sham 1.8 min. 6.0 min. 12.0min. 1731 Day 17 Day 3 Day 10 Day 25 1732 Day 7 Day 21 Day 1 Day 14 1735Day 18 Day 11 Day 4 N/A 1736 Day 23 Day 2 N/A Day 9 1738 Day 8 Day 15Day 36 Day 25 1739 Day 20 Day 38 Day 30 Day 45 1741 Day 50 Day 35 Day 57Day 42

Results

FIG. 6A show the particle count over time for each animal after itreceived a sham dosage. Each timepoint typically represents the mean ofat least three particle count determinations. The data in FIG. 6A showsthat certain individual animals inherently produce more particles thanothers (“superspreaders”). Additionally, the data show that throughoutthe assessment period, quiescently breathing anesthetized animalsmaintain a relatively stable exhaled particle output (see e.g. Animalnos. 1731, 1735, 1738, 1739, and 1741).

FIG. 6B represents the mean percent change in exhaled particle countsover time following each treatment. Each data point represents the meanof six to seven measurements from the treatment group. All animals hadreturned to baseline by 180 minutes post treatment. The data suggestthat the 6.0 minute treatment period provides an adequate dose toprevent the exhalation of particles for at least 150 minutespost-treatment. The other treatments appear to be either too short ortoo long to provide an effective, lasting suppression of aerosolexhalation.

CONCLUSION

The study conducted in cattle demonstrates the efficacy of isotonicsaline on the formation of exhaled aerosols in spontaneously breathinganimals relevant to livestock herds. Based on the results, delivery ofisotonic saline can markedly diminish the number of expired aerosolparticles in a dose-responsive manner. In addition, this large animaldosing system allows for repeated controlled exposures. By using eachanimal as its own control via the daily pre-exposure baseline and thesham exposure, the inherent variability associated with particleexhalation can be understood. The data suggests that 6.0 minutes ofsaline nebulization diminishes particle exhalation for a minimum of 120minutes in cows.

1. A method for treating a respiratory infection in a subject comprisingadministering to the subject a therapeutically effective amount of anon-surfactant aerosol formulation comprising an active agent and apharmaceutically acceptable diluent, said diluent containing about0.9-5% (w/w) NaCl.
 2. The method of claim 1, wherein the active agent isselected from the group consisting of an antibiotic, an antihistamine,and an antiviral agent.
 3. The method of claim 1, wherein thenon-surfactant aerosol formulation is a substantially aqueous solution.4. The method of claim 1, wherein the non-surfactant aerosol formulationis in the form of a suspension.
 5. The method of claim 1, wherein thenon-surfactant aerosol formulation is in the form of a dry powder. 6.The method of claim 1, wherein the subject is human.
 7. The method ofclaim 1, wherein the respiratory infection is selected from the groupconsisting of tuberculosis, SARS, influenza, cytomegalovirus,respiratory syncytial virus, African swine fever, coronavirus,rhinovirus, tularemia, bubonic plague, anthrax, bronchiolitis and footand mouth disease.
 8. The method of claim 7, wherein the respiratoryinfection is influenza.
 9. The method of claim 1, wherein the subject isat risk of developing a respiratory infection.
 10. The method of claim1, wherein said diluent contains about 0.9% (w/w) NaCl.
 11. The methodof claim 1, wherein said aerosol formulation is administered to thesubject by a nebulizer.
 12. The method of claim 1, wherein saidnon-surfactant aerosol formulation does not induce expectoration in thesubject.
 13. The method of claim 1, wherein said non-surfactant aerosolformulation is administered to the subject for a duration of between 2and 20 minutes.
 14. The method of claim 1, wherein said non-surfactantaerosol formulation is administered to the subject for a duration ofbetween 10 and 108 seconds.
 15. The method of claim 1, wherein thenon-surfactant aerosol formulation is effective to dilute endogenousairway lining fluid, endogenous surfactant fluid, to alter surfacetension of endogenous surfactant fluid, to alter surface elasticity ofendogenous surfactant fluid, to alter surface viscosity of endogenousairway lining fluid in the subject or to alter bulk viscosity ofendogenous airway lining fluid in the subject.
 16. A method for reducingthe exhalation of pulmonary infection particles in a subject having apulmonary infection comprising administering to the subject atherapeutically effective amount of a non-surfactant aerosol formulationcomprising an active agent and a pharmaceutically acceptable diluent,said diluent containing about 0.9-5% (w/w) NaCl.
 17. The method of claim16, wherein the active agent is selected from the group consisting of anantibiotic, an antihistamine, and an antiviral agent.
 18. The method ofclaim 16, wherein the pulmonary infection particles are between about 80to 120 nm in diameter.
 19. The method of claim 16, wherein the pulmonaryinfection particles are greater than about 120 nm in diameter.
 20. Themethod of claim 16, wherein the subject is human.
 21. The method ofclaim 16, wherein the respiratory disease is selected from the groupconsisting of tuberculosis, SARS, influenza, cytomegalovirus,respiratory syncytial virus, African swine fever, coronavirus,rhinovirus, tularemia, bubonic plague, anthrax, bronchiolitis, foot andmouth disease, allergy, asthma, cystic fibrosis, chronic bronchitis,emphysema, and acute respiratory distress syndrome.
 22. The method ofclaim 21, wherein the respiratory disease is influenza.
 23. The methodof claim 16, wherein the non-surfactant aerosol formulation is effectiveto dilute endogenous airway lining fluid, endogenous surfactant fluid,to alter surface tension of endogenous surfactant fluid, to altersurface elasticity of endogenous surfactant fluid, to alter surfaceviscosity of endogenous airway lining fluid in the subject or to alterbulk viscosity of endogenous airway lining fluid in the subject.
 24. Amethod of decreasing exhalation of particles in an individual having arespiratory disease comprising administering to the individual aneffective amount of a biocompatible formulation selected from the groupconsisting of a hypertonic saline formulation containing an active agentand an isotonic saline solution comprising other salts or sugars,wherein the formulation is administered effective to dilute endogenousairway lining fluid, endogenous surfactant fluid, to alter surfacetension of endogenous surfactant fluid, to alter surface elasticity ofendogenous surfactant fluid, to alter surface viscosity of endogenousairway lining fluid in the subject or to alter bulk viscosity ofendogenous airway lining fluid, thereby decreasing bioaerosolexhalation.
 25. The method of claim 24, wherein the respiratory diseaseis an infection selected from the group consisting of tuberculosis,SARS, influenza, cytomegalovirus, respiratory syncytial virus, Africanswine fever, coronavirus, rhinovirus, tularemia, bubonic plague,anthrax, bronchiolitis and foot and mouth disease.
 26. The method ofclaim 24, wherein the respiratory disease is selected from the groupconsisting of allergy, asthma, cystic fibrosis, chronic bronchitis,emphysema, and acute respiratory distress syndrome.
 27. The method ofclaim 24, wherein the formulation creates a coating on the respiratorytract lining fluid.
 28. The method of claim 24, wherein said formulationcontains about 0.9% (w/w) NaCl.
 29. The method of claim 24, wherein saidformulation is administered to the subject as an aerosol.
 30. The methodof claim 24, wherein said formulation is administered to the subject bya nebulizer.